Cobalt-Catalyzed Selective Hydrogenation of Nitriles to Secondary Imines

Article abstract of DOI:10.1021/acs.orglett.8b02744

The first example of cobalt-catalyzed selective hydrogenation of nitriles to secondary imines is reported. The results demonstrate the significantly different selectivity compared with the previously reported cobalt catalytic system during the nitrile hydrogenation. A variety of aromatic and aliphatic nitriles are hydrogenated to the corresponding secondary imines.

Full text of DOI:10.1021/acs.orglett.8b02744

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cobalt-Catalyzed Selective Hydrogenation of Nitriles to Secondary
Imines
Huaifeng Li,† Abdullah Al-Dakhil,† Daniel Lupp,† Sandeep Suryabhan Gholap,† Zhiping Lai,†
Lan-Chang Liang,*,‡,§ and Kuo-Wei Huang*,†
†Division of Physical Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi
Arabia
‡Department of Chemistry, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
§Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
S
* Supporting Information
ABSTRACT: The first example of cobalt-catalyzed selective
hydrogenation of nitriles to secondary imines is reported. The
results demonstrate the significantly different selectivity
compared with the previously reported cobalt catalytic system
during the nitrile hydrogenation. A variety of aromatic and
aliphatic nitriles are hydrogenated to the corresponding
secondary imines.
atalytic hydrogenation of nitriles is a significant but
tolerance.4 To overcome these limitations, the homogeneous
catalytic systems for the selective hydrogenation of nitriles to
primary,1,5 secondary,6 or tertiary amines7 have been explored.
In addition, an attractive and challenging goal is the direct
hydrogenation of nitriles to selectively produce secondary
imines. In this respect, only a few catalytic systems have been
developed. The first report of a homogeneous hydrogenation
of nitriles to secondary imines was published by Garcia and co-
workers using a nickel catalyst in 2009.8 However, this
methodology is operated at high temperatures (140−180 °C)
and limited to mono- and dicyanobenzene derivatives. Berke
and co-workers demonstrated the hydrogenation of nitriles to
the corresponding secondary imines as major products
catalyzed by molybdenum and tungsten pincer complexes,
yielding a mixture of primary amine, primary imine, and
secondary imine and requiring high temperature and pressure
(140 °C, 60 bar of H2).9 Recently, Prechtl and co-workers
reported the hydrogenation of nitriles to secondary imines
catalyzed by a ruthenium pincer complex under mild
conditions, while this method is limited to only a few
substrates.5c In addition, Sabo-Etienne observed the formation
of N-benzylidenebenzylamine during the hydrogenation of
benzonitrile catalyzed by a ruthenium system.10 Very recently,
the selective hydrogenation of nitriles to secondary imines
catalyzed by an iron pincer complex with a broad substrate
scope was reported by Milstein and co-workers, but the
drawbacks of this catalytic system are the multistep synthetic
operations and the requirement of toxic carbon monoxide gas
1
Cchallenging process in industry and academia.
The
resulting product imines and amines are widely used as
intermediates and precursors for pharmaceuticals and agro-
chemicals.2 However, selectivity is a crucial issue in this
methodology. Primary and secondary imines and a mixture of
primary, secondary, and even tertiary amines are usually
formed during the catalytic hydrogenation of nitriles (Scheme
1). The catalysts play a key role in selectivity,1 and thus the
development of a highly active and selective catalyst is
desirable for the nitrile hydrogenation reactions.
Scheme 1. Possible Product Formation during Nitrile
Hydrogenation
Traditionally, stoichiometric amounts of metal hydrides or
hydrosilanes are used to reduce the nitriles.3 However, these
methods are not environmentally benign due to the generation
of stoichiometric amounts of waste metal salts. In industry, the
hydrogenation of nitriles is carried out by using heterogeneous
catalysts typically based on Co, Ni, and Pd, but they often
suffer from low selectivity and limited functional group
Received: August 28, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02744
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
during the course of the preparation of the catalyst.11 Hence,
selective hydrogenation of nitriles to secondary imines under
mild reaction conditions using well-defined, environmentally
benign, and readily accessible catalysts remains challenging.
Owing to their sustainability, low cost, and earth abundance,
efforts have been made toward the development of cobalt
catalysts for homogeneous hydrogenation.12 Nevertheless,
catalytic hydrogenation of nitriles based on Co complexes
are less developed. Milstein and co-workers reported the first
homogeneous Co-catalyzed hydrogenation of nitriles to
primary amines in 2015 (Scheme 2).5e Very recently, the
Scheme 2. Cobalt-Catalyzed Hydrogenation of Nitrile
Figure 2. X-ray structures of complexes Co1, Co2, and Co3 at 30%
ellipsoid probability. Hydrogen atoms are omitted for clarity. Selected
bond lengths (Å). Co1: Co1−Cl1 2.1975(8), Co1−N2 1.925(2),
Co1−P1 2.1250(7), Co1−P2 2.1131(7). Co2: Co1−Cl1 2.2501(7),
Co1−Cl2 2.4439(7), Co1−N2 1.9654(18), Co1−P1 2.2279(8),
Co1−P2 2.2174(7). Co3: Co1−Cl1 2.240(2), Co1−Cl2 2.423(2),
Co1−N2 1.975(6), Co1−P1 2.210(2), Co1−P2 2.217(2). Selected
bond angles (deg). Co1: Cl1−Co1−N2 178.24(7), P1−Co1−P2
169.21(3), Cl1−Co1−P1 96.26(3), Cl1−Co1−P2 94.54(3), N2−
Co1−P1 85.51(7), N2−Co1−P2 83.70(7). Co2: Cl1−Co1−N2
161.91(6), P1−Co1−P2 166.46(3), Cl1−Co1−Cl2 103.13(2). Co3:
Cl1−Co1−N2 165.51(18), P1−Co1−P2 167.47(9), Cl1−Co1−Cl2
99.08(8).
groups of Fout and Beller developed nitrile hydrogenation
reactions to afford primary amines, catalyzed by a cobalt
bis(carbene) pincer complex and cobalt/tetradentate phos-
phine catalyst system, respectively (Scheme 2).5k,l To our
knowledge, Co-catalyzed selective hydrogenation of nitriles to
secondary imines has not been reported thus far.13 As part of
our ongoing interest in the PN3-pincer complexes and their
catalysis,14 herein, we present the first selective hydrogenation
of nitriles to secondary imines catalyzed by a well-defined and
readily accessible PN3P cobalt pincer complex (Scheme 2).
Pyridine-based pincer complexes are of particular interest
especially since the discovery of the new mode of metal−ligand
cooperation involving the aromatization−dearomatization
process of the ligands.15 In this context, the straightforward
synthesis of cobalt complexes Co1, Co2,16 and Co3 (Figure 1)
toluene at 130 °C under 62 atm of H2 for 24 h resulted in
complete conversion of the 1a with the formation of 85% N-
benzylidenebenzylamine (2a) and 11% of benzylamine (3a)
(Table 1, entry 1). Cobalt complex Co2 or Co3 could also be
employed as catalyst for the selective hydrogenation of 1a to
secondary imines 2a, albeit with lower yield and selectivity
(Table 1, entries 2 and 3). It is noteworthy that these results
are strikingly different from those of the analogous PNP cobalt
complex Co4 (having CH2 rather than NH spacers) by
Milstein and co-workers, enabling the catalytic hydrogenation
of benzonitrile (1a) to benzylamine 3a as a major product with
the formation of a small amount of 2a (Scheme 3).5e In
addition, the X-ray structure of this PNP cobalt complex Co4
exhibits a highly distorted square-pyramidal structure with two
chlorides coordinating to the cobalt center (see the Supporting
Information),19 different from that of complex Co1 in spite of
only the small change on the spacers. These comparisons
indicate the critical role of the ligand modification. We have
previously demonstrated that the PN3P−Ru complexes showed
the significantly enhanced reactivities for the dehydrogenation
of amines to imines compared to those of the Milstein PNPs.20
Such unique catalytic performances prompted us to further
optimize the conditions. A control experiment showed that no
reaction occurred under these conditions in the absence of the
catalyst (Table 1, entry 4). Without the base, a mixture of 2a
(36%), 3a (13%), and N-benzylbenzylamine (4a, 47%) were
obtained, which suggested the vital importance of base for the
selectivity control during the catalytic hydrogenation of nitriles
(Table 1, entry 5). In contrast to toluene, the use of THF as
solvent favored the formation of primary amine 3a as a major
product (Table 1, entry 6). Benzene was found to give a similar
yield of 2a, along with the formation of a small amount of 3a
(Table 1, entry 7). Lowering the H2 pressure to 41 atm under
analogous reaction conditions led to lower selectivity toward
2a (Table 1, entry 8). Significantly, only 2a was detected by
GC−MS at a lower temperature of 80 °C, despite the lower
Figure 1. PN3P Co pincer complexes Co1, Co2, and Co3.
could be achieved by the treatment of CoCl2 with 1.1 equiv of
the corresponding pincer ligand at room temperature in THF.
These cobalt(II) complexes were crystallographically charac-
terized (Figure 2). The X-ray structure of Co1 shows a rare
square-planar Co(II) complex with a noncoordinating chloride
anion,17 while the complexes Co218 and Co3 adopt a distorted
square-pyramidal structure with two chlorides coordinating to
the cobalt center, probably because of the steric bulk of the
four tert-butyl groups of the PN3P ligand in Co1.
The hydrogenation of benzonitrile (1a) was chosen as the
model reaction to test the activity of the cobalt complexes. The
use of complex Co1 (1 mol %) and KOtBu (4 mol %) in
B
DOI: 10.1021/acs.orglett.8b02744
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Organic Letters
Letter
a
Table 1. Optimization Studies for the Hydrogenation of Benzonitrile
b
yield (%)
b
entry
catalyst
solvent
ρH2 (atm)
temp (° C)
t (h)
conv (%)
2a
85
56
64
trace
36
25
81
65
63
73
3a
4a
1
2
3
Co1
Co2
Co3
toluene
toluene
toluene
toluene
toluene
THF
benzene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
62
62
62
62
62
62
62
41
62
102
62
62
62
62
130
130
130
130
130
130
130
130
80
24
24
24
24
24
24
24
24
24
41
24
36
48
48
>99
>99
>99
<1
>99
>99
>99
>99
63
73
88
94
>99
11
41
33
trace
13
71
c
4
d
5
Co1
Co1
Co1
Co1
Co1
Co1
Co1
Co1
Co1
Co1
47
6
7
8
9
13
30
10
80
e
11
100
100
100
110
85
90
97
91
e
12
e
13
14
>99
6
a
b
Condition: [Co] complex (0.01 mmol), 1a (1 mmol), KOtBu (0.04 mmol), solvent (6.0 mL). Conversions and yields were determined by 1H
c
NMR spectroscopy of the crude reaction mixture using CH2Br2 as the internal standard or GC−MS using m-xylene as internal standard. Without
catalyst. Without KOtBu. Benzaldimine formation was observed (<5%).
d
e
Scheme 3. Hydrogenation of Benzonitrile Catalyzed by Co4
Table 2. Hydrogenation of Nitriles to Secondary Imines
Catalyzed by Co1
a
conversion of 1a (Table 1, entry 9). Increasing the H2 pressure
to 102 atm did not significantly improve the conversion of 1a
(73%, Table 1, entry 10). Gratifyingly, the conversion could be
improved considerably when the reaction temperature was
increased from 80 to 100 °C (Table 1, entry 11). By extending
the reaction time at 100 °C, the full conversion could be
achieved with excellent selectivity to 2a (Table 1, entries 12
and 13). The reaction is quite sensitive to the reaction
temperature, and when the reaction was carried out at 110 °C,
primary amine 3a was formed (Table 1, entry 14).
Using entry 13 in Table 1 as the standard reaction
conditions, the substrate scope of this cobalt-catalyzed
hydrogenation of nitriles was explored. As shown in Table 2,
various benzonitriles containing either electron-donating or
-withdrawing substituents were hydrogenated in good yields.
Hydrogenation of 4-fluorobenzonitrile (1b) afforded N-(4-
fluorobenzylidene)-4-fluorobenzylaminein (2b) in excellent
yield under the standard reaction conditions (Table 2, entry
2). In the cases of 4-chlorobenzonitrile (1c) and 4-
bromobenzonitrile (1d), the corresponding secondary imines
were formed in 82% and 84% yields, respectively, with the
halide substituent being tolerated (Table 2, entries 3 and 4).
Hydrogenation of 4-(trifluoromethyl)benzonitrile (1e) re-
sulted in 93% conversion and 71% isolated yield of
corresponding secondary imine at a slightly higher temper-
ature, 110 °C (Table 2, entry 5). 4-Methylbenzonitrile (1f)
and 3-methylbenzonitrile (1g) were hydrogenated to their
corresponding secondary imines in excellent conversions with
good selectivities (Table 2, entries 6 and 7). Further, the
catalytic reactions of 4-methoxybenzonitrile (1h) and 4-N,N-
dimethylbenzonitrile (1i) yielded the corresponding secondary
a
Conditions: Co1 (0.01 mmol), 1a (1 mmol), KOtBu (0.04 mmol),
b
toluene (6.0 mL), 62 atm of H2, 100 °C. Conversions and yields
were determined by H NMR spectroscopy of the crude reaction
1
mixture using CH2Br2 as the internal standard or GC−MS using m-
c
xylene as internal standard. Yield of isolated product in parentheses.
d
e
110 °C. 130 °C.
C
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Letter
imines in good to moderate yields (Table 2, entries 8 and 9).
Similarly, 2-naphthonitrile (1j) furnished 81% of the
corresponding imine under the same hydrogenation conditions
(Table 2, entry 10). Notably, heterocyclic nitrile 3-
pyridinecarbonitrile (1k), which is usually regarded as a
challenging substrate due to its chelating character, could also
be hydrogenated, although in lower conversion (74%) and
yield (49%) (Table 2, entry 11).21 Aliphatic nitriles are usually
considered to be more challenging substrates because of the
possible base-induced condensation side reactions. When the
aliphatic nitriles were subjected to the hydrogenation reaction,
the reaction was found to be sluggish (Table 2, entries 12−14).
Under the catalytic conditions, hydrogenation of secondary
alkyl nitrile cyclohexylcarbonitrile gave the corresponding
imine in only 61% yield detected by GC−MS (Table 2,
entry 12). Under analogous reaction conditions, valeronitrile
and butyronitrile produced 53% and 47% yields of the
corresponding second imines (Table 2, entries 13 and 14).
To gain further understanding of the high selectivity toward
secondary imines in this catalytic system, the control
experiments were carried out (Scheme 4). When secondary
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02744.
■
S
Experimental details, and characterization data (PDF)
Accession Codes
CCDC 1858908, 1858909 and 1859265 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44
1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: lcliang@mail.nsysu.edu.tw.
*E-mail: hkw@kaust.edu.sa.
ORCID
Scheme 4. Control Experiments
Sandeep Suryabhan Gholap: 0000-0003-2080-1510
Zhiping Lai: 0000-0001-9555-6009
Lan-Chang Liang: 0000-0002-8185-2824
Kuo-Wei Huang: 0000-0003-1900-2658
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by King Abdullah University of
Science and Technology (KAUST) and the Ministry of
Science and Technology of Taiwan (MOST 106-2113-M-
110-003).
imine 2a was subjected to the standard hydrogenation
conditions, further hydrogenation did not occur. This result
is consistent with the high selectivity for the formation of
secondary imines. When hydrogenation of 1a was conducted
in the presence of p-toluidine, besides the formation of 2a,
benzylidene-p-toluidine was also produced as a major product,
suggesting that the intermediate primary imine was formed
during the hydrogenation reaction. Considering these ob-
servations mentioned above, the reaction step to form
intermediate primary imine might be rate-determining for
the whole reaction (Scheme 1). Attempts to isolate the active
catalyst during the reactions were not successful, but the
plausible catalyst activation may involve a dearomatized cobalt
complex formed via the deprotonation of one of the N−H
arms of Co1 under the reaction conditions, which can then
react with H2 to afford a cobalt hydride species for the
hydrogenation of the nitriles.14,22
In conclusion, we have developed the first cobalt-catalyzed
selective hydrogenation of nitriles to secondary imines under
relatively mild conditions with generally high conversions and
high selectivity. Importantly, the well-defined and readily
accessible PN3P cobalt pincer complex showed significantly
different selectivity with the existing cobalt catalytic system
during the nitriles hydrogenation, providing another case with
respect to the crucial role that ligand modification may have. In
light of the catalytic performance and the simple preparation,
complex Co1 holds promise as an economical catalyst for the
selective hydrogenation of nitriles. Attempts to isolate the
catalytically active species and theoretical investigations on this
system are in progress and will be reported in due course.
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Org. Lett. XXXX, XXX, XXX−XXX